Induced Kidney Disease Research Articles

Fate mapping reveals compartment-specific clonal expansion of mononuclear phagocytes during kidney disease

Fate mapping reveals compartment-specific clonal expansion of mononuclear phagocytes during kidney disease

Impact of N-acetylcysteine supplementation on skeletal muscle myopathy in a mouse model of access-related hand dysfunction

Introduction: Hemodialysis is a life-line therapy for end-stage kidney disease patients that requires long-term arteriovenous access. Arteriovenous fistula (AVF) is the most durable and commonly employed access strategy. However, access-related hand dysfunction (ARHD) including ischemia, weakness, and neuromotor discoordination is prevalent (~50%) following AVF placement. Unfortunately, there are no pre-emptive non-surgical therapeutic studies available. We hypothesized that N-acetylcysteine (NAC) supplementation would attenuate hindlimb disability in a mouse model of ARHD. Methods: Adult male and female C57BL/6J mice (N=9/group) were fed adenine diet to induce kidney disease. Thereafter, animals were randomly allocated to receive NAC (150 mg/kg in 0.2 ml of 0.9% saline) or placebo (0.2 ml of saline) via oral gavage beginning 3 days prior to the AVF surgery and until euthanasia. Limb perfusion to the ischemic hindlimb and hindlimb grip strength were assessed post-operatively (POD) in vivo. Muscle contractile and mitochondrial function, and histological assessments of muscle and the neuromuscular junction were also performed. Results: Laser Doppler perfusion to the ventral paw was decreased immediately after AVF creation on the left common iliac artery (~25% of the contralateral limb) and recovered (~40-60%) at POD13 without a treatment effect. NAC treatment improved muscle mass in the tibialis anterior (TA) (+13~21%, P<0.05) and soleus (+17~21%, P<0.05) muscles in both male and female mice compared with placebo-treated animals. NAC female, not male, mice had significant improvement in grip strength (~20% greater at POD4 and POD12, P<0.05) and maximal mitochondrial respiration (~30% higher at POD14, P<0.05) compared with control animals. Muscle contractile function and myofiber area and capillarization in TA and soleus muscles were similar between NAC and placebo groups (P>0.05). Interestingly, the area of the post-synaptic acetylcholine receptor clusters was significantly greater in the animals that received NAC treatment (+10~22%, P<0.05) in both male and female mice. Conclusion: Daily treatment with a thiol reducing antioxidant, NAC, has beneficial effects on the recovery of muscle mass and neuromuscular junction morphology in both male and female mice with additional improvement in grip strength and mitochondrial function in female mice suggesting a potential therapeutic strategy targeting antioxidant defense to ameliorate ARHD. Funding Support: National Institutes of Health grant R01HL148597 and American Heart Association grant POST903198. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Loss of Soluble (Pro) Renin Receptor Attenuates Adenine Induced Kidney Disease

Loss of Soluble (Pro) Renin Receptor Attenuates Adenine Induced Kidney Disease

Crystal structure and cellular functions of uPAR dimer

Receptor dimerization of urokinase-type plasminogen activator receptor (uPAR) was previously identified at protein level and on cell surface. Recently, a dimeric form of mouse uPAR isoform 2 was proposed to induce kidney disease. Here, we report the crystal structure of human uPAR dimer at 2.96 Å. The structure reveals enormous conformational changes of the dimer compared to the monomeric structure: D1 of uPAR opens up into a large expanded ring that captures a β-hairpin loop of a neighboring uPAR to form an expanded β-sheet, leading to an elongated, highly intertwined dimeric uPAR. Based on the structure, we identify E49P as a mutation promoting dimer formation. The mutation increases receptor binding to the amino terminal fragment of its primary ligand uPA, induces the receptor to distribute to the basal membrane, promotes cell proliferation, and alters cell morphology via β1 integrin signaling. These results reveal the structural basis for uPAR dimerization, its effect on cellular functions, and provide a basis to further study this multifunctional receptor.

Hantavirus Induced Kidney Disease

Hantavirus induced hemorrhagic fever with renal syndrome (HFRS) is an emerging viral zoonosis affecting up to 200,000 humans annually worldwide. This review article is focused on recent advances in the mechanism, epidemiology, diagnosis, and treatment of hantavirus induced HFRS. The importance of interactions between viral and host factors in the design of therapeutic strategies is discussed. Hantavirus induced HFRS is characterized by thrombocytopenia and proteinuria of varying severities. The mechanism of kidney injury appears immunopathological with characteristic deterioration of endothelial cell function and compromised barrier functions of the vasculature. Although multidisciplinary research efforts have provided insights about the loss of cellular contact in the endothelium leading to increased permeability, the details of the molecular mechanisms remain poorly understood. The epidemiology of hantavirus induced renal failure is associated with viral species and the geographical location of the natural host of the virus. The development of vaccine and antiviral therapeutics is necessary to avoid potentially severe outbreaks of this zoonotic illness in the future. The recent groundbreaking approach to the SARS-CoV-2 mRNA vaccine has revolutionized the general field of vaccinology and has provided new directions for the use of this promising platform for widespread vaccine development, including the development of hantavirus mRNA vaccine. The combinational therapies specifically targeted to inhibit hantavirus replication and vascular permeability in infected patients will likely improve the disease outcome.

COVID-19 induced renal injury differs from that in other viral-infections

Abstract Background: Kidney injuries caused by several viral diseases have been reported worldwide among all age groups, races, and genders. Of particular importance is coronavirus disease 2019 (COVID-19), and its prevalence in communities infecting all patient populations with symptoms ranging from asymptomatic to severe, including complications and mortality. Methods: Data were acquired from PubMed, Scopus, Google Scholar, Centers for Disease Prevention and Control (CDC), and Lexi-Comp using the following search terms: “COVID-19 and renal pathology,” “COVID-19 induced kidney disease,” “Viral infection induced kidney disease,” and “Viral infection induced renal damage.” Titles and abstracts were manually analyzed as per the exclusion and inclusion criteria of relevant articles; relevance of articles included studies on the pathology of a specific viral infection and the impact of the virus on the adult renal system. Results: The mechanisms for renal disease due to COVID-19 include direct renal tubular injury, cytokine storm, inflammation, thrombosis vs. acute tubular necrosis, thrombotic events, and direct renal injury. Although some mechanisms behind renal dysfunction among the studied viral infections are similar, the prevalence rates of kidney injury or damage differ. This might be described by recommended prophylactic and therapeutic approaches that can alter the viral infection characteristics and possibly the impact a particular organ system. Conclusion: The patient population at risk was old in age and had a high body mass index. The mechanisms associated with renal dysfunction are similar, including direct renal injury through angiotensin converting enzyme 2 (ACE2) entry, inflammation, and thrombosis. The renal pathology of coronaviruses that differs from that of other prevalent viral infections is the activation of cytokine storm, which causes elevations of a greater number and different kinds of cytokines than other viral infections.

Distinct APOL1 functions in trypanosomes and kidney podocytes

The human serum protein apolipoprotein L1 (APOL1) kills Trypanosoma brucei but not the sleeping sickness agent Trypanosoma rhodesiense. APOL1 C-terminal variants can kill T. rhodesiense but they also induce kidney disease. Given topological and functional differences between intracellular and extracellular APOL1 isoforms, I propose that trypanolysis and kidney disease result from distinct APOL1 activities.

MANTI: Automated Annotation of Protein N-Termini for Rapid Interpretation of N-Terminome Data Sets.

Site-specific proteolytic processing is an important, irreversible post-translational protein modification with implications in many diseases. Enrichment of protein N-terminal peptides followed by mass spectrometry-based identification and quantification enables proteome-wide characterization of proteolytic processes and protease substrates but is challenged by the lack of specific annotation tools. A common problem is, for example, ambiguous matches of identified peptides to multiple protein entries in the databases used for identification. We developed MaxQuant Advanced N-termini Interpreter (MANTI), a standalone Perl software with an optional graphical user interface that validates and annotates N-terminal peptides identified by database searches with the popular MaxQuant software package by integrating information from multiple data sources. MANTI utilizes diverse annotation information in a multistep decision process to assign a conservative preferred protein entry for each N-terminal peptide, enabling automated classification according to the likely origin and determines significant changes in N-terminal peptide abundance. Auxiliary R scripts included in the software package summarize and visualize key aspects of the data. To showcase the utility of MANTI, we generated two large-scale TAILS N-terminome data sets from two different animal models of chemically and genetically induced kidney disease, puromycin adenonucleoside-treated rats (PAN), and heterozygous Wilms Tumor protein 1 mice (WT1). MANTI enabled rapid validation and autonomous annotation of >10 000 identified terminal peptides, revealing novel proteolytic proteoforms in 905 and 644 proteins, respectively. Quantitative analysis indicated that proteolytic activities with similar sequence specificity are involved in the pathogenesis of kidney injury and proteinuria in both models, whereas coagulation processes and complement activation were specifically induced after chemical injury.

N-acetylecysteine: The multiuse antioxidant

N-acetylcysteine (NAC) is an acetylated variant of the amino acid L-cysteine, is an effective antidote able to increase cell protection against oxidative stress , it acts as an antioxidant by restoring the pool of intracellular reduced glutathione, which is often depleted as a consequence of increased status of oxidative stress and inflammation. It has reducing and antioxidant properties, acting as a direct scavenger of ROS (reactive oxygen species). NAC is available in different dosage forms for different indications.Many studies stated other uses of NAC such as mucolytic action which is useful in obstructive airway , nasal sinus diseases as it liquefies bacterial biofilms ( antibacterial action), decrease radio contrast induced kidney disease, treatment of many neuropsychiatric diseases like Alzheimer's disease, bipolar disorder, major depressive disorder, obsessive-compulsive disorder, schizophrenia, specific drug addictions (cocaine) and a certain form of epilepsy (progressive myoclonic) through central mechanisms, and improved fertility outcome in both males and females.

PREVALENCE OF MICROALBUMINURIA IN TYPE - 2 DIABETES MELLITUS: A HOSPITAL BASED STUDY

Aim: Microalbuminuria (MAU) has been shown to be a risk factor for nephropathy in patients with type 2 diabetes. In this study, we aimed to explore the association between MAU and other risk factors in the development of diabetic nephropathy with type 2 diabetes. Methods: Five twenty one patients with type 2 diabetes were recruited in this study. Medical records were used to collect data of age, duration of diabetes, Body Mass Index (BMI) and history of hypertension. Blood samples were collected after 12 hours overnight fasting to estimate fasting blood glucose (FBG), Glycosylated haemoglobin (HbA1C), serum creatinine, and serum uric acid. MAU was quantified using the dipstick method in early morning urine samples. Results: Out of 521 subjects 37.5% (186 subjects) were found to be suffering from MAU. Systolic and diastolic blood pressure (p<0.001), HbA1C (p<0.001) and fasting blood glucose (p<0.001) were significantly higher in subjects with MAU as compared to normoalbuminuria subjects. Further, on multiple logistic regression analysis it was observed that duration of diabetes, systolic and diastolic blood pressure, serum creatinine and FBG are associated with MAU. Conclusion: The overall prevalence of the MAU was high in the present study, which necessitates for early detection of nephropathy to reduce the burden of diabetes induced kidney disease in the future.

APOL1 C-Terminal Variants May Trigger Kidney Disease through Interference with APOL3 Control of Actomyosin

SummaryThe C-terminal variants G1 and G2 of apolipoprotein L1 (APOL1) confer human resistance to the sleeping sickness parasite Trypanosoma rhodesiense, but they also increase the risk of kidney disease. APOL1 and APOL3 are death-promoting proteins that are partially associated with the endoplasmic reticulum and Golgi membranes. We report that in podocytes, either APOL1 C-terminal helix truncation (APOL1Δ) or APOL3 deletion (APOL3KO) induces similar actomyosin reorganization linked to the inhibition of phosphatidylinositol-4-phosphate [PI(4)P] synthesis by the Golgi PI(4)-kinase IIIB (PI4KB). Both APOL1 and APOL3 can form K+ channels, but only APOL3 exhibits Ca2+-dependent binding of high affinity to neuronal calcium sensor-1 (NCS-1), promoting NCS-1-PI4KB interaction and stimulating PI4KB activity. Alteration of the APOL1 C-terminal helix triggers APOL1 unfolding and increased binding to APOL3, affecting APOL3-NCS-1 interaction. Since the podocytes of G1 and G2 patients exhibit an APOL1Δ or APOL3KO-like phenotype, APOL1 C-terminal variants may induce kidney disease by preventing APOL3 from activating PI4KB, with consecutive actomyosin reorganization of podocytes.

A virus-induced kidney disease model based on organ-on-a-chip: Pathogenesis exploration of virus-related renal dysfunctions

Renal dysfunctions usually happen in viral infections and many viruses specially infect distal renal tubules, however the pathogenesis remains unknown. Here, in order to explore the pathogenesis of virus-related renal dysfunctions, a Pseudorabies Virus (PrV) induced kidney disease model was built on a distal tubule-on-a-chip (DTC), for the first time. The barrier structure and Na reabsorption of distal renal tubules were successfully reconstituted in DTCs. After PrV infection, results showed electrolyte regulation dysfunction in Na reabsorption for the disordered Na transporters, the broken reabsorption barrier, and the transformed microvilli. And it would lead to virus induced serum electrolyte abnormalities. This work brought us a new cognition about the advantages of organ-on-a-chip (OOC) in virus research, for it had given us a better insight into the pathogenesis of virus induced dysfunctions, based on its unique ability in function reproduction.

MON-011 A CASE SERIES OF MONOCLONAL GAMMOPATHY OF RENAL SIGNIFICANCE (MGRS) IN THE CONTEXT OF MONOCLONAL IMMUNOGLOBULIN DETECTION

Monoclonal gammopathy of renal significance (MGRS) highlights the fact that a small amount of monoclonal immunoglobulin (MIg) not meeting the criteria of multiple myeloma might induce kidney disease if the MIg shows affinity to the kidneys. However, the detection of MIg can be difficult when it remains low levels. Here, we present a case series study of MGRS carried out over the past five years, which involved a comparison of the methods of MIg detection. Twelve patients (male: n=7, age: 56.8±12.9 years old) with biopsy-proven MGRS were enrolled between 2013 and 2018. Their underlying hematological disorders were as follows: monoclonal gammopathy of undetermined significance (MGUS, n=8), chronic myeloid leukemia (CML, n=1), and follicular lymphoma (n=1). Variable data were reviewed based on medical records, including immunoelectrophoresis (IEP), the serum-free light chain (FLC) ratio, and immunofluorescent (IF) pathological findings (trans-sectional descriptive study). Histological diagnoses were as follows: AL amyloidosis (n=6), fibrillary glomerulopathy (n=1), light chain deposit disease (LCDD, n=1), light chain proximal tubulopathy (LCPT, n=1), and proliferative glomerulonephritis with monoclonal IG deposits (PGNMID, n=3). An IF study revealed deposition of lambda (AL amyloidosis: n=5/6, LCDD: n=1/1), kappa (AL amyloidosis: n=1/6, LCPT: n=1/1), IgG1-kappa (PGNMID: n=1/3), and IgG3-kappa (PGNMID: n=2/3), with only one case showing no deposition (fibrillary glomerulopathy). Laboratory tests showed a mean estimated GFR of 57.8±25.1 mL/min/1.73m2, serum albumin of 2.6±1.2 g/dL, and a urine protein per creatinine ratio of 6.4±3.8 g/g creatinine, suggesting six cases of nephrotic syndrome (AL amyloidosis: n=4/6, LCDD and PGNMID: n=1/3). IEP showed that serum and urine MIg were present in 20% and 64%of these cases, respectively. On the other hand, abnormal FLC ratios have been detected in 70% of these case. These results were consistent with the observed depositions in the IF study. Among the PGNMID cases, two cases with no history of hematologic disorder showed no MIg by both IEP and the FLC ratio, whereas one case with follicular lymphoma, which we had previously reported (Minakawa. BMJ case report. 2016), showed detectable MIg by the FLC ratio but not by the serum or urine IEP. In summary, PGNMID might arise even during the course of a normal immune response, and its MIg-paucity is well-known. The current study suggests that FLC might be a more sensitive or at least equivalent tool to detect low levels of MIg compared with IEP for MGRS, especially in the case of PGNMID.

Apolipoprotein-1 (Apol-1) Gene Polymorphism in Hypertensive Nephroscelerosis Egyptian Patients

AbstractBackground: Arterial Hypertension (AHTN) represents a major public health problem for its high frequency among the unselected population and, particularly, for its strong association with cardiovascular morbidity and mortality. Progressive renal disease has always been comprised among the possible end-organ damage-related to hypertension. The APOL1 G1 and G2 risk variants are highly associated with non-diabetic non-HIV associated forms of kidney disease, and in particular FSGS and hypertensive nephropathy.Aim of Study: To study influence of the APOL1 gene variants (G1 and G2) on the hypertensive induced kidney disease among Egyptian Patients.Subjects and Methods: In the current study, we examined 88 adult patients (>!18 years old) of both sexes with essential hypertension for >!5 years and classified into two groups: Group I: Included fifty-three patients with essential hyperten-sion (Bl.Pr. >!140/90) who have normal kidney function. Group II: Included thirty-five patients with essential hypertension (Bl.Pr. >!140/90) who have impaired kidney function mostly attributed to HTN. Essential hypertension was diagnosed if the patient gave history of hypertension, with antihypertensive medications or if Bl.Pr. >!140/90 at the time of examination without definite cause. All patients were subjected to thorough medical history taking, physical examination, and many investigations were done as well as APOL1 gene study using Polymerase Chain Reaction (PCR).Results: There is significant statistical difference between both groups as regard APOL1 G1 rs73885319, G1 rs60910195 and G2 rs71785313 genotypes and alleles (the abnormal genotypes AG, GG, TG, DI, DD are more frequent in patients with hypertensive nephroscelerosis; Group II). Most patients with hypertensive nephroscelerosis (Group II) carry two risk alleles and showed more decline estimated Glomerular Filter-ation Rate (eGFR) than Group I despite matching in the hypertension duration and severity.Conclusion: APOL1 G1 rs73885319, G1 rs60910195 and G2 rs71785313 gene polymorphism is associated with in-creased risk of hypertensive induced kidney disease among Egyptian patients. Most patients with hypertensive nephros-celerosis (Group II) showed more decline in e-GFR than group I despite matching in the hypertension duration and severity.

The Causes of Chronic Kidney Disease in Adults in a Developing Country

Introduction: Diabetes mellitus (DM) and hypertension (HTN) are considered as the leading causes of CKD all around the world. But the causes of CKD differ from region to region. In developing countries the population is heterogeneous therefore regional causes of CKD need to be evaluated. Material and method: This cross sectional study included all adult CKD patients, who visited to nephrology service in two tertiary care hospitals in metropolitan city Karachi in Pakistan. The sociodemographic data was collected by interview through a structured questionnaire while laboratory data was collected from patients records. Results: Diabetic nephropathy (DNP) was the main cause of CKD (37.5%) followed by hypertensive nephropathy (17.1%) and obstructive nephropathy (ONP) (12.7%). ONP and hereditary disorders (HD) were more prevalent in males than females (70. 1% vs. 29.9%) and (75% vs. 25%) respectively, while urinary tract infection (UTI), drug induced kidney disease and tubulointerstitial nephritis (TIN) were more common in females than in males (87.5% vs. 12.5%), (75.8% vs.24.2%) and (64.7% vs. 35.3%) respectively. Gender, area of residence and socioeconomic status were the factors which affect the cause of CKD (p ≤ 0.05). Conclusion: DNP and hypertensive nephropathy were more prevalent in urban, educated males with high socioeconomic background. On the other hand CKD of unknown etiology and stone diseases were more common in rural, uneducated, males with low socioeconomic background.

Drug Induced Kidney Disease

Drug Induced Kidney Disease

Phenotype standardization for drug-induced kidney disease

Drug induced kidney disease is a frequent cause of renal dysfunction; however, there are no standards to identify and characterize the spectrum of these disorders. We convened a panel of international, adult and pediatric, nephrologists and pharmacists to develop standardized phenotypes for drug induced kidney disease as part of the phenotype standardization project initiated by the International Serious Adverse Events Consortium. We propose four phenotypes of drug induced kidney disease based on clinical presentation: acute kidney injury, glomerular, tubular and nephrolithiasis, along with primary and secondary clinical criteria to support the phenotype definition, and a time course based on the KDIGO/AKIN definitions of acute kidney injury, acute kidney disease and chronic kidney disease. Establishing causality in drug induced kidney disease is challenging and requires knowledge of the biological plausibility for the specific drug, mechanism of injury, time course and assessment of competing risk factors. These phenotypes provide a consistent framework for clinicians, investigators, industry and regulatory agencies to evaluate drug nephrotoxicity across various settings. We believe that this is first step to recognizing drug induced kidney disease and developing strategies to prevent and manage this condition.

Psychiatric and medical adverse events for kidney transplant recipients with lithium induced kidney disease

Background: The purpose of this study is to describe post-transplant psychiatric and medical adverse events for kidney transplant (KT) recipients with a history of lithium induced kidney disease. According to the United Network for Organ Sharing (UNOS) as of January 2015 there have been 208 kidney transplantations done in the USA for this condition and 227 are currently waiting for a kidney. Considering the evidence that decompensated psychiatric conditionsmay interferewith post-transplant outcomes, there is a concern about the risk of posttransplant adverse events in this population. To our knowledge, at this time there is no information about medical or psychiatric course post transplantation for kidney recipients with a history of lithium toxicity. Method: Retrospective study of patients who received kidney transplantation for lithium induced kidney disease at Yale Transplantation Center. The following electronic documents were reviewed: discharge summaries, admission assessments, clinic visit notes, social work evaluations, psychiatric evaluations, counts of hospitalizations and clinic visits, and laboratory tests (immunosuppressant levels). We are presenting the descriptive analysis of this information. Results: We identified a total of 12 patients who received a KT for a primary diagnosis of lithium induced kidney disease at our center between 1/1/2004 and 12/31/2014. Eight (66%) were male and all were Caucasian. The most common co-occurring medical condition was hypertension 8 (66%) followed by hypothyroidism 4 (33.3%). Six (50%) had received hemodialysis before transplantation and 2 (16.5%) had received peritoneal dialysis, for an average dialysis duration of 2.35 years (±2.81). The post KT follow-up was 3.11 years (±2.26). Eleven (91.6%) had a diagnosis of Bipolar I disorder. The most commonly prescribed psychotropic medications were Lamotrigine (4 cases), followed by Quetiapine, Aripiprazole and Divalproex (3 cases each). One patient was continued on lithium through dialysis and after transplant. There were a total of 3 psychiatric hospitalizations corresponding to 0.08 hospitalizations per patient per year (PPY), 25 medical hospitalizations (average 2 per patient ±1.9) or 0.66PPY; infections 0.08 PPY, rejection 0.02PPY); instances of subtherapeutic medications level 0.21PPY. There was one death in the group. There were no instances of graft loss. Conclusion: Post-transplant exacerbations of psychiatric illness, psychiatric hospitalizations, graft loss, infections, and death were rare in patients receiving KT for lithium induced kidney disease at our center. Studying a higher number of patients with longer post-transplant follow-up, possible through multicenter registry, would provide more accurate information about the psychiatric and medical course of this group of KT recipients.

Receptor-Mediated Endocytosis Is a Trojan Horse in Light-Chain Nephrotoxicity

Receptor-Mediated Endocytosis Is a Trojan Horse in Light-Chain Nephrotoxicity

Early biomarkers of cadmium exposure and nephrotoxicity

As the risks of cadmium (Cd)-induced kidney disease have become increasingly apparent, much attention has been focused on the development and use of sensitive biomarkers of Cd nephrotoxicity. The purpose of this review is to briefly summarize the current state of Cd biomarker research. The review includes overviews of the toxicokinetics of Cd, the mechanisms of Cd-induced proximal tubule injury, and mechanistic summaries of some of the biomarkers (N-acetyl-β-D-glucosamidase; β(2)-microglubulin, metallothionein, etc.) that have been most widely used in monitoring of human populations for Cd exposure and nephrotoxicity. In addition, several novel biomarkers (kidney injury molecule-1, α-glutathione-S-transferase and insulin) that offer the potential for improved biomonitoring of Cd-exposed populations are discussed.